N,N-disubstituted diazocycloalkanes

Abstract

N,N-Disubstituted diazocycloalkanes of the formula I (R 1 =halogen, R 2 =(C 3 -C 8 )-cycloalkyl, R 3 =(C 1 -C 4 )-alkoxy or (C 1 -C 4 )-haloalkoxy group, m is 1 or 2 and n is 1 or 2, have affinity for serotonergic receptors. These compounds and their enantiomers, diastereoisomers, N-oxides, polymorphs, solvates and pharmaceutically acceptable salts are useful in the treatment of patients with neuromuscular dysfunction of the lower urinary tract and diseases related to 5-HT 1A receptor.

1 . A compound having the general formula I  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  represents a halogen atom,  
 R 2  represents a (C 3 -C 8 )-cycloalkyl group,  
 R 3  represents a (C 1 -C 4 )-alkoxy,  
 m is 1 or 2, and  
 n is 1,  
 or an enantiomer, optical isomer, diastereomer, N-oxide, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof.  
 
   
   
       2 . A compound according to  claim 1  that is a serotonin 5HT 1A  receptor antagonist.  
   
   
       3 . The compound according to  claim 1  in which R 1  represents a fluorine atom.  
   
   
       4 . The compound according to  claim 3  in which the fluorine atom is at the 2-position of the phenyl ring to which it is attached.  
   
   
       5 . The compound according to  claim 1  in which R 2  represents a cyclohexyl group.  
   
   
       6 - 9 . (canceled)  
   
   
       10 . The compound according to  claim 1  in which the carbon atom bearing the R 1 -phenyl group has the (R) configuration.  
   
   
       11 . A compound according to  claim 1  in which the carbon atom bearing the R 2  and hydroxy groups has the (S) configuration.  
   
   
       12 . The compound according to  claim 11  in which the carbon atom bearing the R 1 -phenyl group has the (R) configuration.  
   
   
       13 . The compound according to  claim 1  which is 1-[4-cyclohexyl-4-hydroxy-3-(2-fluorophenyl)-butyl]-4-(2-methoxyphenyl)-piperazine in the form of any of its isolated stereoisomers: 
 1-[(3R,4S)-4-cyclohexyl-4-hydroxy-3-(2-fluorophenyl)-butyl]-4-(2-methoxyphenyl)-piperazine,    1-[(3S,4R)-4-cyclohexyl-4-hydroxy-3-(2-fluorophenyl)-butyl]-4-(2-methoxyphenyl)-piperazine,    1-[(3R,4R)-4-cyclohexyl-4-hydroxy-3-(2-fluorophenyl)-butyl]-4-(2-methoxyphenyl)-piperazine, or    1-[(3S,4S)-4-cyclohexyl-4-hydroxy-3-(2-fluorophenyl)-butyl]-4-(2-methoxyphenyl)-piperazine, 
 or a mixture of any two or more thereof in any proportion.  
   
   
   
       14 . The compound of  claim 13  wherein said mixture comprises a predetermined amount of at least one of said stereoisomers.  
   
   
       15 - 16 . (canceled)  
   
   
       17 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable diluent or carrier.  
   
   
       18 . A method for treating disorders of the urinary tract in a mammal in need thereof, comprising administering an effective amount of a compound according to  claim 1 , to ameliorate at least one condition selected from the group consisting of urinary urgency, overactive bladder, increased urinary frequency, decreased urinary compliance, cystitis, incontinence, urine leakage, enuresis, dysuria, urinary hesitancy and difficulty in emptying the bladder.  
   
   
       19 . The method of  claim 18  wherein the administered compound is 1-[4-cyclohexyl-4-hydroxy-3-(2-fluorophenyl)-butyl]-4-(2-methoxyphenyl)-piperazine in the form of any of its isolated stereoisomers: 
 1-[(3R,4S)-4-cyclohexyl-4-hydroxy-3-(2-fluorophenyl)-butyl]-4-(2-methoxyphenyl)-piperazine,    1-[(3S,4R)-4-cyclohexyl-4-hydroxy-3-(2-fluorophenyl)-butyl]-4-(2-methoxyphenyl)-piperazine,    1-[(3R,4R)-4-cyclohexyl-4-hydroxy-3-(2-fluorophenyl)-butyl]-4-(2-methoxyphenyl)-piperazine, or    1-[(3S,4S)-4-cyclohexyl-4-hydroxy-3-(2-fluorophenyl)-butyl]-4-(2-methoxyphenyl)-piperazine, 
 or a mixture of any two or more thereof in any proportion.  
   
   
   
       20 . (canceled)  
   
   
       21 . The method according to  claim 18  in which said compound is administered in combination with an antimuscarinic.  
   
   
       22 . The method according to  claim 18  in which said compound is administered in combination with an α 1 -adrenergic antagonist.  
   
   
       23 . The method according to  claim 18  in which said mammal is a human.  
   
   
       24 . The method according to claims  18  in which said compound is administered via an oral, enteral, intravenous, intramuscular, subcutaneous, transmucosal, transdermal, or inhalation route.  
   
   
       25 . The method according to  claim 18  wherein said compound is administered in a predetermined amount.  
   
   
       26 - 27 . (canceled)  
   
   
       28 . The compound according to  claim 1  in which R 1  represents a fluorine atom and R 2  represents a cyclohexyl group.